Smooth muscle cells are a developmentally complex population. Smooth muscle cells arise in multiple regions of the embryo from different precursor populations. For example, studies in chick/quail chimeras have shown that unlike smooth muscle cells in the coronary arteries, smooth muscle cells in the great vessels are derived from a subpopulation of mesenchymal neural crest cells (Hood et al. (1992) Anat. Rec. 234:291-300; Rosenquist et al. (1990) Ann. NY Acad. Sci. 588:106-119; Kirby et al. (1983) Science 220:1059-1061; Le Lievre et al (1975) J. Embryol. Exp. Morphol. 34:125-154; herein incorporated by reference in their entirety.) Furthermore, the smooth muscle cells in most visceral organs, including those of the respiratory system, are thought to originate from local mesenchyme (Cunha et al. (1992) Epith. Cell Biol. 1:76-83, herein incorporated by reference).
Unlike skeletal and cardiac muscle cells, where cell differentiation is accompanied by stable expression of muscle-specific genes (Weintraub et al. (1991) Science 251:761-766 and Olson et al. (1992) Genes & Dev. 4:1454-1461, herein incorporated by reference in their entirety), smooth muscle cells display remarkable phenotypic plasticity, and retain the capacity to re-enter the cell cycle (Schwartz et al (1986) Circ. Res. 58:427-444). This unusual characteristic of smooth muscle cell phenotypic modulation is often associated with the loss of many smooth muscle cell-specific markers (Glukhova et al (1991) Am. J. Physiol. 261:78-80; Frid et al (1992) Dev. Biol. 153:185-193; herein incorporated by reference). Such alterations in smooth muscle cell proliferation and differentiation are associated with a variety of vascular diseases including atherosclerosis, restenosis following angioplasty, and hypertension.
Smooth muscle proliferation is associated with numerous pulmonary disorders such as asthma, airway hyperactivity, idiopathic pulmonary hypertension, pulmonary hypertension, secondary pulmonary hypertension, COPD, and pulmonary hypotension. According to the Centers for Disease Control and Prevention, asthma affects almost six percent of American children and over six percent of American adults. Pulmonary hypertension resulted in 7,139 deaths and 174,854 hospital visits in 1998. Currently, there is a low survival prognosis and no cure or simple treatment for pulmonary hypertension (Gerberding, J. (2003) Report to Congress Pulmonary Hypertension Centers for Disease Control and Prevention, herein incorporated by reference). Numerous disorders including, but not limited to emphysema, bronchitis, scleroderma, CREST, and congenital disorders, result in secondary pulmonary hypertension. Additionally, the N.I.H. reports that chronic obstructive pulmonary disorder is the fourth leading cause of death in the U.S. (N.I.H. Publication No. 03-5229, March 2003, herein incorporated by reference.)
Thus, there is a need in the art for a better understanding of the molecular mechanisms that regulate smooth muscle cell proliferation and differentiation, especially in respect to pulmonary disease. Development of methods of regulating smooth muscle proliferation is desirable. Development of methods of modulating pulmonary disorders is desirable. Development of methods of modulating pulmonary smooth muscle cell related disorders is particularly desirable.